<p>Grape stems, or stalks, are lignocellulosic by-products removed during the destemming process to reduce astringency in wine production. These by-products are a notable source of minerals and polyphenolic compounds, such as phenolic acids, stilbenes, proanthocyanidins and catechin derivatives, flavonols, flavones, and anthocyanins. These bioactive compounds have been associated with several beneficial effects on human health, including the promotion of wound healing and antimicrobial, anti-inflammatory, anti-aging, anti-cancer, and antioxidant activities. Despite this potential, grape stems are still underutilised and are commonly disposed of through composting, landfilling, landfarming, or diverted to animal feed. This review offers an updated and detailed overview of the polyphenolic composition and biological activities of grape stems, highlighting their potential for application in innovative products. Their use could contribute to the advancement of sustainable practices through circular economy strategies and industrial symbiosis.</p>